4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles

ABSTRACT

4-Arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles, useful as analgesic agents, are prepared by reaction of a 3-arylcarbonyl-2-methylnitrobenzene with DMF dimethyl acetal; reductive cyclization of the product with hydrogen over a catalyst; and N-alkylation of the resulting 4-arylcarbonylindole with an appropriate 4-(halo-lower-alkyl)morpholine in the presence of a strong base.

This application is a division of application Ser. No. 013,313, filed2/11/87, now U.S. Pat. No. 4,840,950.

BACKGROUND OF THE INVENTION

This invention relates to4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles which areuseful as analgesics.

INFORMATION DISCLOSURE STATEMENT

Bell U.S. Pat. No. 4,581,354 discloses3-arylcarbonyl1-(amino-lower-alkyl)-1H-indoles useful as analgesic,anti-rheumatic and anti-inflammatory agents.

Deschamps et al. U.S. Pat. No. 3,946,029 discloses1-(amino-lower-alkyl)-2-lower-alkyl-3-(2-, 3- and4-pyridylcarbonyl)-1H-indoles which are stated to possess fibrinolyticand anti-inflammatory activities.

Croce, Ann. di Chim. 63, 29-35 (1973) discloses1(3-aminopropyl)-3-benzoyl-2-methyl-1H-indole for which no utility isdisclosed.

SUMMARY OF THE INVENTION

We have found that certain4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles, which may beconsidered analogous to substituted benzophenone derivatives, haveanalgesic activity and are thus useful as analgesics.

Accordingly, in a composition aspect, the invention relates to4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles and theiracid-addition salts

In a further composition aspect, the invention relates to compositionsfor the relief of pain containing an analgesically effective amount of a4-arylcarbonyl1-[(4-morpholinyl)-lower-alkyl]-1H-indole.

In a method aspect, the invention relates to a method of use of the said4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles for the reliefof pain.

In a process aspect, the invention relates to a process for preparingthe said 4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles whichcomprises reaction of a 3-arylcarbonyl-2-methylnitrobenzene withdimethylformamide dimethyl acetal; reductive cyclization of the productwith hydrogen over a catalyst; and N-alkylation of the resulting4-arylcarbonyl indole with an appropriate 4-(halo-lower-alkyl)morpholinein the presence of a strong base.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

More specifically, this invention relates to4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles, useful asanalgesics, and having the structural formula: ##STR1## where Ar islower-alkoxyphenyl or 1-naphthyl and Alk is lower-alkylene containingfrom two to four carbon atoms.

Preferred compounds within the ambit of formula I as defined above arethose where Ar is 4-lower-alkoxyphenyl or 1-naphthyl and Alk is1,2-ethylene or 1,3-propylene.

As used herein the term lower-alkoxy includes methoxy, ethoxy, propoxyand isopropoxy, and the term lower-alkylene includes straight orbranched lower-alkyl, i.e. 1,2 ethylene, 1-methyl-1,2-ethylene,2-methyl-1,2ethylene, 1,3-propylene, 2-methyl-1,3-propylene,3-methyl1,3-propylene and 1,4-butylene.

The compounds of the invention are prepared by reaction of a4-arylcarbonylindole of formula II hereinbelow with an appropriate4-(halo-lower-alkyl)morpholine in the presence of a strong base, such asan alkali metal hydride or an alkali metal amide. The reaction ispreferably carried out in an organic solvent inert under the conditionsof the reaction, such as dimethylformamide (hereinafter DMF), toluene orxylene, and at temperatures from around ambient up to the boiling pointof the solvent A preferred base is sodium hydride, a preferred solventis DMF, and it is preferred to carry out the reaction at the boilingpoint of the solvent.

The 4-arylcarbonylindoles of formula II in turn are prepared by reactionof a 2-methyl-3-nitrobenzoyl halide with a lower-alkoxybenzene ornaphthalene under Friedel-Crafts reaction conditions in the presence ofaluminum chloride; reaction of the resulting3-arylcarbonyl-2-methylnitrobenzene with DMF dimethyl acetal; andcyclization of the resulting3-arylcarbonyl-2-(2dimethylaminoethenyl)nitrobenzene by catalyticreduction.

The Friedel-Crafts reaction of a 2-methyl-3-nitrobenzoyl halide with alower-alkoxybenzene or naphthalene is carried out in an organic solventinert under the conditions of the reaction, such as methylenedichloride, ethylene dichloride, 1,1,2,2-tetrachloroethane or benzene Itis preferred to bring the reactants together at ambient temperature andthen to heat the mixture at the boiling point of the solvent. Apreferred solvent is methylene dichloride.

The reaction of the 3-arylcarbonyl-2-methylnitrobenzene with DMFdimethyl acetal is carried out by heating under reflux a solution of theformer with a two to four molar excess of the latter in an organicsolvent inert under the conditions of the reaction Preferred solventsare DMF and dioxane.

The reductive cyclization of the3-arylcarbonyl-2-(2-dimethylaminoethenyl)nitrobenzene is carried out inan organic solvent inert under the conditions of the reaction, forexample ethyl acetate or a lower-alkanol, such as methanol, ethanol orisopropanol, at ambient temperature and at hydrogen pressures in therange from around 50 to 100 p.s.i.g. Ethyl acetate or ethanol arepreferred solvents, and it is preferred to carry out the reduction undera hydrogen pressure around 50 p.s.i.g. Preferred catalysts arepalladium-on-charcoal or Raney nickel.

The overall synthetic sequence described above is represented by thereaction scheme: ##STR2## where X represents halogen and Ar and Alk havethe meanings given above.

The compounds of the invention in free base form can be converted to theacid-addition salt forms by interaction of the bases with an acid. Inlike manner, the free bases can be regenerated from the acid-additionsalt forms in conventional manner, that is by treating the salts withcold, weak aqueous bases, for example alkali metal carbonates and alkalimetal bicarbonates. The bases thus regenerated can be interacted withthe same or a different acid to give back the same or a differentacid-addition salt. Thus the novel bases and all of their acid-additionsalts are readily interconvertible.

It will thus be appreciated that formula I not only represents thestructural configuration of the bases of formula I but is alsorepresentative of the structural entity which is common to all thecompounds of formula I, whether in the form of the free bases or in theform of the acid-addition salts of the bases. It has been found that, byvirtue of this common structural entity the bases of formula I and theiracid-addition salts have inherent pharmacological activity of a type tobe more fully described hereinbelow. This inherent pharmacologicalactivity can be enjoyed in useful form for pharmaceutical purposes byemploying the free bases themselves or the acid-addition salts formedfrom pharmaceutically acceptable acids, that is, acids whose anions areinnocuous to the animal organism in effective doses of the salts so thatbeneficial properties inherent in the common structural entityrepresented by the free bases are not vitiated by side effectsascribable to the anions.

In utilizing this pharmacological activity of the salts of theinvention, it is preferred, of course, to use pharmaceuticallyacceptable salts. Although water insolubility, high toxicity or lack ofcrystalline character may make some particular salt species unsuitableor less desirable for use as such in a given pharmaceutical application,the water-insoluble or toxic salts can be converted to the correspondingpharmaceutically acceptable bases by decomposition of the salts withaqueous base as explained above, or alternatively they can be convertedto any desired pharmaceutically acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example by ion-exchangeprocedures.

Moreover, apart from their usefulness in pharmaceutical applications,the salts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures Like all of theacid-addition salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate the pharmaceuticallyacceptable free bases by reaction of the salts with aqueous base, oralternatively they can be converted to a pharmaceutically acceptableacid-addition salt by, for example, ion-exchange procedures.

The novel feature of the compounds of the invention, then, resides inthe concept of the bases and the cationic form of the new4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles of formula Iand not in any particular acid moiety or acid anion associated with thesalt form of the compounds; rather, the acid moieties or anions whichcan be associated with the salt forms are in themselves neither novelnor critical and therefore can be any acid anion or acid-like substancecapable of salt formation with the bases.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid,1-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid,mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid,sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid,2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamicacid, methanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,diethylphosphonic acid, p-aminophenylarsinic acid, phenylstibnic acid,phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,perchloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdicacid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid,barbituric acid, boron trifluoride and the like.

The acid-addition salts are prepared by reacting the free base and theacid in an organic solvent and isolating the salt directly or byconcentration of the solution.

In standard pharmacological test procedures the4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles of formula Ihave been found to possess analgesic activity and are thus useful asanalgesics.

The test procedures used to determine the analgesic activity of thecompounds have been described in detail in the prior art and are asfollows: The acetylcholine-induced abdominal constriction test, which isa primary analgesic screening test designed to measure the ability of atest agent to suppress acetylcholine-induced abdominal constriction inmice, described by Collier et al., Brit. J Pharmacol. Chemotherap. 32,295 (1968) and the rotorod performance test, which is a test designed tomeasure neurotoxicity of a test compound, described by Dunham et al., J.Pharm. Sci. 46, 206-209 (1957).

The 4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles of theinvention can be prepared for pharmaceutical use by incorporation of thecompounds in unit dosage form as tablets or capsules for oral orparenteral administration either alone or in combination with suitableadjuvants such as calcium carbonate, starch, lactose, talc, magnesiumstearate, gum acacia and the like. Still further, the compounds can beformulated for oral or parenteral administration either in aqueoussolutions of the water soluble salts or in aqueous alcohol, glycol oroil solutions or oil-water emulsions in the same manner as conventionalmedicinal substances are prepared

The percentages of active component in such compositions may be variedso that a suitable dosage is obtained. The dosage administered to aparticular patient is variable, depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus only be determined by theclinician after a consideration of all criteria and using his bestjudgment on the patient's behalf.

The molecular structures of the4-arylcarbonyl-1[(4-morpholinyl)-lower-alkyl]-1H-indoles of theinvention were assigned on the basis of their infrared, ultraviolet andNMR spectra. The structures were confirmed by the correspondence betweencalculated and found values for elementary analyses for the elements

The following examples will further illustrate the invention without,however, limiting it thereto All melting points are uncorrected.

EXEMPLARY DISCLOSURE Preparation of Intermediates Preparation 1A

To a suspension of 95.6 g (0.716 mole) of aluminum chloride in 500 ml ofmethylene dichloride was added, rapidly and with stirring, a solution of110.1 g (0.551 mole) of 2-methyl-3-nitrobenzoyl chloride in 400 ml ofmethylene dichloride The mixture was then transferred to an additionfunnel, added with stirring to a solution of 9.8 g (0.551 mole) ofanisole over a thirty minute period, and the reaction mixture thenheated under reflux for two hours. The mixture was decomposed by thecareful addition, with stirring, of 1 liter of water and then filtered.The organic layer was separated from the aqueous layer, dried and takento dryness, and the residue recrystallized from ethyl acetate to give102.9 g of 3-(4-methoxybenzoyl)2-methylnitrobenzene, m.p. 110°-113° C.Anal., Calcd. for C₁₅ H₁₃ NO₄ : C, 66.41; H, 4.83; N, 5.16.5. Found: C,66.33; H, 4.95; N, 4.98.

Preparation 1B

Following a procedure similar to that described in Preparation 1A above,71.1 g (0.554 mole) of naphthalene in 500 ml of methylene dichloride wastreated, over a thirty minute period with stirring, with a mixture of110.5 g (0.554 mole) of 2-methyl-3-nitrobenzoyl chloride and 96.0 g(0.72 mole) of aluminum chloride in 900 ml of methylene dichloride. Thecrude product isolated from the reaction mixture crystallized from ethylacetate/hexane. The crystals so-obtained were recrystallized again fromethanol to give material having m.p. 100°-102° C. which, from its nmrspectrum and analyses for the elements, was identified as2-methyl-3-(2-naphthylcarbonyl)nitrobenzene (45% yield).

The combined mother liquors from the isolation of the 2-naphthyl isomerwere taken to dryness and the resulting oil crystallized fromtoluene/hexane to give material which, from its nmr spectrum, wasidentified as 2-methyl-3-(1-naphthylcarbonyl)nitrobenzene in about 30%yield.

Preparation 2A

A solution of 97.9 g (0.36 mole) of3-(4-methoxybenzoyl)-2-methylnitrobenzene and 191 ml (1.45 mole) of DMFdimethyl acetal in 400 ml of DMF was heated under reflux for aboutnineteen hours and the reaction mixture then taken to dryness in vacuoto give 108 g of2-(2-dimethylaminoethenyl)-3-(4-methoxybenzoyl)nitrobenzene as a redoil.

Preparation 2B

Following a procedure similar to that described in Preparation 2A above,57 g (0.195 mole) of 2-methyl-3(1-naphthylcarbonyl)nitrobenzene and 103ml (0.784 mole) of DMF dimethyl acetal in 300 ml of DMF was heated underreflux for seventeen hours and then taken to dryness to give2-(2-dimethylaminoethenyl)-3-(1-naphthylcarbonyl)nitrobenzene as an oil.

Preparation 3A

A solution of 32 g. (0.098 mole) of2-(2-dimethylaminoethenyl)-3-(4-methoxybenzoyl)nitrobenzene in 200 ml ofethyl acetate was treated with 5 g of 10% palladium-on-charcoal, and thestarting material reduced with hydrogen under 50 p.s.i.g. The mixturewas then filtered, the filtrate taken to dryness, and the residuerecrystallized from ethyl acetate to give 18.1 g of4-(4-methoxybenzoyl)indole. Another sample, similarly prepared byreduction of the starting material with Raney nickel in ethanol,afforded material having m.p. 148°-152° C. Anal., Calc. for C₁₅ H₁₁ NO:C, 76.48; H, 5.21; N, 5.57. Found: C, 76.73; H, 5.27; N, 5.58.

Preparation 3B

Following a procedure similar to that described in Preparation 3A above,72 g (0.21 mole) of2-(2-dimethylaminoethenyl)-3-(1-naphthylcarbonyl)nitrobenzene wasreduced with hydrogen over 13.5 g of 10% palladium-on-charcoal in ethylacetate under 40 p.s.i.g. Removal of the catalyst by filtration andevaporation of the filtrate to dryness afforded 45 g of4-(1-naphthylcarbonyl)indole as an oil, which was used as such inExample 1C without further purification

Preparation of the Final Products Example 1A

To a stirred mixture of 3.5 g (0.0887 mole) of a 60% suspension ofsodium hydride in hexane in 50 ml of DMF was added 18.1 g (0.0721 mole)of 4-(4-methoxybenzoyl)indole The mixture was then treated with asolution containing 0.18 mole of 4-(2-chloroethyl)morpholine in t-butylmethyl ether (prepared by extraction of the free base from a suspensionof 35.5 g of the corresponding hydrochloride in saturated sodiumbicarbonate). When addition was complete, the reaction mixture washeated under reflux for about twelve hours, treated with 1500 ml ofwater and extracted with 500 ml of ethyl acetate. The combined organicextracts, on drying and evaporation to dryness, afforded an oil whichwas dissolved in 250 ml of ethyl acetate and treated with 50 ml ofethereal hydrogen chloride. The material which separated was collectedand recrystallized from ethanol to give 20.3 g of4-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole hydrochloride,m.p. 177°-180 ° C.

Anal., Calc. for C₂₂ H₂₄ N₂ O₃.HCl: C, 65.91; H, 6.29; N, 6.99; Cl,8.84. Found: C,66.23, H, 6.32; N, 7.18; Cl, 8.91.

Example 1B

Following a procedure similar to that described in Example 1A above, 10g (0.0398 mole) of 4-(4-methoxybenzoyl)indole in 200 ml of DMF wasalkylated with 16.3 g of 4-(3-chloropropyl)morpholine in the presence of1.9 g (0.0478 mole) of a 60% suspension of sodium hydride in hexane. Theproduct was isolated in the form of the hydrochloride salt to give 11.2g of 4-(4-methoxybenzoyl)-1-[3-(4morpholinyl)propyl]-1H-indolehydrochloride, m.p.168°-171° C.

Anal.,Calc. for C₂₃ H₂₆ N₂ O₃.HCl: C, 66 58; H, 6.56; N, 6.75; Cl, 8.54.Found: C, 66.30; H, 6.61; N, 6.65; Cl, 8.73.

Example 1C

Following a procedure similar to that described in Example 1A above, 45g (0.17 mole) of 4-(1-naphthylcarbonyl)indole in 500 ml of DMF wasalkylated with about 0.425 mole of 4-(2-chloroethyl)morpholine (preparedby extraction of the free base into 200 ml of t-butyl methyl ether froma suspension of about 79 g of the corresponding hydrochloride in sodiumbicarbonate) in the presence of about 10 g of a 60% dispersion of sodiumhydride in hexane. The product was isolated in the form of thep-toluene-sulfonate which was crystallized from ethyl acetate to give5.3 g of 1-[2-(4-morpholinyl)ethyl]-4-(1-naphthylcarbonyl)-1H-indolep-toluenesulfonate hydrate 3:1, m.p. 86°-88° C. Anal., Calc. for C₃₂ H₃₂N₂ O₅ S.1/3H₂ O: C, 68.31; H, 5.85; N, 4.98; S, 5.76. Found: C, 66.66;H, 5.15; N, 4.86; S, 5.67.

BIOLOGICAL TEST RESULTS

The 4-arylcarbonyl-1-[(4-morpholinyl)-lower-alkyl]-1H-indoles of theinvention were tested in the acetylcholine-induced abdominalconstriction test (Ach), which gives a measure of antinociceptiveactivity, and the rotorod assay (R.R.), which gives a measure ofneurotoxicity and CNS impairment. The results, expressed in terms of theED₅₀ 's obtained on oral administration in the acetylcholine test and asthe ratio of the rotorod (R.R.):Ach ED₅₀ 's, are given in the followingtable:

    ______________________________________                                        Compound     Ach         R.R.: Ach Ratio                                      ______________________________________                                        Ex. 1A       46          3.1                                                               93%/100 (s.c.)                                                   Ex. 1B       63          2.8                                                  Ex. 1C       16          --                                                   ______________________________________                                    

We claim:
 1. A method for the relief of pain in a patient requiring suchtreatment which comprises administering orally or parenterally to suchpatient a medicament in solid or liquid dosage form containing, as theactive component thereof, an analgesically effective amount of acompound having the formula: ##STR3## where Ar is lower-alkoxyphenyl or1-naphthyl, and Alk is lower-alkylene containing from one to four carbonatoms or a pharmaceutically acceptable acid-addition salt thereof.